Robert Y L Zee1, Paul M Ridker, Daniel I Chasman. 1. Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. rzee@rics.bwh.harvard.edu
Abstract
BACKGROUND: Candidate genes associated with telomere length maintenance, an important molecular marker for biological aging, represent potential risk predictors for cardiovascular disease (CVD). To date, no prospective data are available. METHODS: The associations between 154 tag-single nucleotide polymorphisms (tSNPs) of 11 telomere-associated candidate genes (TERT, POT1, TNKS, TERF1, TNKS2, UCP2, TEP1, ACD, TERF2, TERF2IP, and TERC) were investigated in 23,294 Caucasian participants of the Women's Genome Health Study. All were free of known CVD and cancer at baseline. The primary outcome measure was a composite CVD end point (incident ischemic stroke, myocardial infarction (MI), or death due to ischemic CVD); other measures were incident MI and ischemic stroke. During follow-up, 1178 total incident CVD, 315 incident MI cases, and 323 incident ischemic stroke events were identified. Multivariable Cox regression analysis and a haplotype-based approach were performed to investigate the relationship between genotypes/haplotypes and CVD risk, assuming an additive model. RESULTS: In a marker-by-marker analysis, 7 (TEP1, TNKS, and ACD), 11 (TEP1, ACD, and TERT), and 24 (TEP1, TNKS, TERT, TERF2IP, TNKS2, and UCP2) SNPs were associated-at the level of p < 0.05-with the total CVD, MI, and ischemic stroke risk, respectively. Further analysis using a haplotype-based approach showed similar findings. Although none remained significant after the correction of multiple testing, the false discovery rate analysis revealed 28% of the nominally significant SNPs with true associations in relation to ischemic stroke risk. CONCLUSIONS: The present large prospective study encourages further investigation of the biological role of telomere-associated pathway genes in the pathogenesis and early assessment of vascular events.
BACKGROUND: Candidate genes associated with telomere length maintenance, an important molecular marker for biological aging, represent potential risk predictors for cardiovascular disease (CVD). To date, no prospective data are available. METHODS: The associations between 154 tag-single nucleotide polymorphisms (tSNPs) of 11 telomere-associated candidate genes (TERT, POT1, TNKS, TERF1, TNKS2, UCP2, TEP1, ACD, TERF2, TERF2IP, and TERC) were investigated in 23,294 Caucasian participants of the Women's Genome Health Study. All were free of known CVD and cancer at baseline. The primary outcome measure was a composite CVD end point (incident ischemic stroke, myocardial infarction (MI), or death due to ischemic CVD); other measures were incident MI and ischemic stroke. During follow-up, 1178 total incident CVD, 315 incident MI cases, and 323 incident ischemic stroke events were identified. Multivariable Cox regression analysis and a haplotype-based approach were performed to investigate the relationship between genotypes/haplotypes and CVD risk, assuming an additive model. RESULTS: In a marker-by-marker analysis, 7 (TEP1, TNKS, and ACD), 11 (TEP1, ACD, and TERT), and 24 (TEP1, TNKS, TERT, TERF2IP, TNKS2, and UCP2) SNPs were associated-at the level of p < 0.05-with the total CVD, MI, and ischemic stroke risk, respectively. Further analysis using a haplotype-based approach showed similar findings. Although none remained significant after the correction of multiple testing, the false discovery rate analysis revealed 28% of the nominally significant SNPs with true associations in relation to ischemic stroke risk. CONCLUSIONS: The present large prospective study encourages further investigation of the biological role of telomere-associated pathway genes in the pathogenesis and early assessment of vascular events.
Authors: Verena Varadi; Annika Brendle; Andreas Brandt; Robert Johansson; Kerstin Enquist; Roger Henriksson; Ulrika Svenson; Björn Tavelin; Göran Roos; Kari Hemminki; Per Lenner; Asta Försti Journal: Eur J Cancer Date: 2009-09-18 Impact factor: 9.162
Authors: Idan Menashe; Dennis Maeder; Montserrat Garcia-Closas; Jonine D Figueroa; Samsiddhi Bhattacharjee; Melissa Rotunno; Peter Kraft; David J Hunter; Stephen J Chanock; Philip S Rosenberg; Nilanjan Chatterjee Journal: Cancer Res Date: 2010-05-11 Impact factor: 12.701
Authors: Paul M Ridker; Nancy R Cook; I-Min Lee; David Gordon; J Michael Gaziano; Joann E Manson; Charles H Hennekens; Julie E Buring Journal: N Engl J Med Date: 2005-03-07 Impact factor: 91.245
Authors: Jing Shen; Marilie D Gammon; Hui-Chen Wu; Mary Beth Terry; Qiao Wang; Patrick T Bradshaw; Susan L Teitelbaum; Alfred I Neugut; Regina M Santella Journal: Cancer Epidemiol Biomarkers Prev Date: 2010-01 Impact factor: 4.254
Authors: Guillaume Paré; Daniel I Chasman; Alexander N Parker; Robert R Y Zee; Anders Mälarstig; Udo Seedorf; Rory Collins; Hugh Watkins; Anders Hamsten; Joseph P Miletich; Paul M Ridker Journal: Circ Cardiovasc Genet Date: 2009-04
Authors: Veryan Codd; Massimo Mangino; Pim van der Harst; Peter S Braund; Michael Kaiser; Alan J Beveridge; Suzanne Rafelt; Jasbir Moore; Chris Nelson; Nicole Soranzo; Guangju Zhai; Ana M Valdes; Hannah Blackburn; Irene Mateo Leach; Rudolf A de Boer; Masayuki Kimura; Abraham Aviv; Alison H Goodall; Willem Ouwehand; Dirk J van Veldhuisen; Wiek H van Gilst; Gerjan Navis; Paul R Burton; Martin D Tobin; Alistair S Hall; John R Thompson; Tim Spector; Nilesh J Samani Journal: Nat Genet Date: 2010-02-07 Impact factor: 38.330
Authors: Daniel I Chasman; Guillaume Paré; Samia Mora; Jemma C Hopewell; Gina Peloso; Robert Clarke; L Adrienne Cupples; Anders Hamsten; Sekar Kathiresan; Anders Mälarstig; José M Ordovas; Samuli Ripatti; Alex N Parker; Joseph P Miletich; Paul M Ridker Journal: PLoS Genet Date: 2009-11-20 Impact factor: 5.917
Authors: Andrea N Burnett-Hartman; Annette L Fitzpatrick; Richard A Kronmal; Bruce M Psaty; Nancy S Jenny; Josh C Bis; Russ P Tracy; Masayuki Kimura; Abraham Aviv Journal: Mech Ageing Dev Date: 2012-03-16 Impact factor: 5.432
Authors: Brian T Joyce; Yinan Zheng; Drew Nannini; Zhou Zhang; Lei Liu; Tao Gao; Masha Kocherginsky; Robert Murphy; Hushan Yang; Chad J Achenbach; Lewis R Roberts; Mirjam Hoxha; Jincheng Shen; Pantel Vokonas; Joel Schwartz; Andrea Baccarelli; Lifang Hou Journal: Cancer Prev Res (Phila) Date: 2018-06-12
Authors: Yun J Sung; Thomas W Winkler; Lisa de Las Fuentes; Amy R Bentley; Michael R Brown; Aldi T Kraja; Karen Schwander; Ioanna Ntalla; Xiuqing Guo; Nora Franceschini; Yingchang Lu; Ching-Yu Cheng; Xueling Sim; Dina Vojinovic; Jonathan Marten; Solomon K Musani; Changwei Li; Mary F Feitosa; Tuomas O Kilpeläinen; Melissa A Richard; Raymond Noordam; Stella Aslibekyan; Hugues Aschard; Traci M Bartz; Rajkumar Dorajoo; Yongmei Liu; Alisa K Manning; Tuomo Rankinen; Albert Vernon Smith; Salman M Tajuddin; Bamidele O Tayo; Helen R Warren; Wei Zhao; Yanhua Zhou; Nana Matoba; Tamar Sofer; Maris Alver; Marzyeh Amini; Mathilde Boissel; Jin Fang Chai; Xu Chen; Jasmin Divers; Ilaria Gandin; Chuan Gao; Franco Giulianini; Anuj Goel; Sarah E Harris; Fernando Pires Hartwig; Andrea R V R Horimoto; Fang-Chi Hsu; Anne U Jackson; Mika Kähönen; Anuradhani Kasturiratne; Brigitte Kühnel; Karin Leander; Wen-Jane Lee; Keng-Hung Lin; Jian 'an Luan; Colin A McKenzie; He Meian; Christopher P Nelson; Rainer Rauramaa; Nicole Schupf; Robert A Scott; Wayne H H Sheu; Alena Stančáková; Fumihiko Takeuchi; Peter J van der Most; Tibor V Varga; Heming Wang; Yajuan Wang; Erin B Ware; Stefan Weiss; Wanqing Wen; Lisa R Yanek; Weihua Zhang; Jing Hua Zhao; Saima Afaq; Tamuno Alfred; Najaf Amin; Dan Arking; Tin Aung; R Graham Barr; Lawrence F Bielak; Eric Boerwinkle; Erwin P Bottinger; Peter S Braund; Jennifer A Brody; Ulrich Broeckel; Claudia P Cabrera; Brian Cade; Yu Caizheng; Archie Campbell; Mickaël Canouil; Aravinda Chakravarti; Ganesh Chauhan; Kaare Christensen; Massimiliano Cocca; Francis S Collins; John M Connell; Renée de Mutsert; H Janaka de Silva; Stephanie Debette; Marcus Dörr; Qing Duan; Charles B Eaton; Georg Ehret; Evangelos Evangelou; Jessica D Faul; Virginia A Fisher; Nita G Forouhi; Oscar H Franco; Yechiel Friedlander; He Gao; Bruna Gigante; Misa Graff; C Charles Gu; Dongfeng Gu; Preeti Gupta; Saskia P Hagenaars; Tamara B Harris; Jiang He; Sami Heikkinen; Chew-Kiat Heng; Makoto Hirata; Albert Hofman; Barbara V Howard; Steven Hunt; Marguerite R Irvin; Yucheng Jia; Roby Joehanes; Anne E Justice; Tomohiro Katsuya; Joel Kaufman; Nicola D Kerrison; Chiea Chuen Khor; Woon-Puay Koh; Heikki A Koistinen; Pirjo Komulainen; Charles Kooperberg; Jose E Krieger; Michiaki Kubo; Johanna Kuusisto; Carl D Langefeld; Claudia Langenberg; Lenore J Launer; Benjamin Lehne; Cora E Lewis; Yize Li; Sing Hui Lim; Shiow Lin; Ching-Ti Liu; Jianjun Liu; Jingmin Liu; Kiang Liu; Yeheng Liu; Marie Loh; Kurt K Lohman; Jirong Long; Tin Louie; Reedik Mägi; Anubha Mahajan; Thomas Meitinger; Andres Metspalu; Lili Milani; Yukihide Momozawa; Andrew P Morris; Thomas H Mosley; Peter Munson; Alison D Murray; Mike A Nalls; Ubaydah Nasri; Jill M Norris; Kari North; Adesola Ogunniyi; Sandosh Padmanabhan; Walter R Palmas; Nicholette D Palmer; James S Pankow; Nancy L Pedersen; Annette Peters; Patricia A Peyser; Ozren Polasek; Olli T Raitakari; Frida Renström; Treva K Rice; Paul M Ridker; Antonietta Robino; Jennifer G Robinson; Lynda M Rose; Igor Rudan; Charumathi Sabanayagam; Babatunde L Salako; Kevin Sandow; Carsten O Schmidt; Pamela J Schreiner; William R Scott; Sudha Seshadri; Peter Sever; Colleen M Sitlani; Jennifer A Smith; Harold Snieder; John M Starr; Konstantin Strauch; Hua Tang; Kent D Taylor; Yik Ying Teo; Yih Chung Tham; André G Uitterlinden; Melanie Waldenberger; Lihua Wang; Ya X Wang; Wen Bin Wei; Christine Williams; Gregory Wilson; Mary K Wojczynski; Jie Yao; Jian-Min Yuan; Alan B Zonderman; Diane M Becker; Michael Boehnke; Donald W Bowden; John C Chambers; Yii-Der Ida Chen; Ulf de Faire; Ian J Deary; Tõnu Esko; Martin Farrall; Terrence Forrester; Paul W Franks; Barry I Freedman; Philippe Froguel; Paolo Gasparini; Christian Gieger; Bernardo Lessa Horta; Yi-Jen Hung; Jost B Jonas; Norihiro Kato; Jaspal S Kooner; Markku Laakso; Terho Lehtimäki; Kae-Woei Liang; Patrik K E Magnusson; Anne B Newman; Albertine J Oldehinkel; Alexandre C Pereira; Susan Redline; Rainer Rettig; Nilesh J Samani; James Scott; Xiao-Ou Shu; Pim van der Harst; Lynne E Wagenknecht; Nicholas J Wareham; Hugh Watkins; David R Weir; Ananda R Wickremasinghe; Tangchun Wu; Wei Zheng; Yoichiro Kamatani; Cathy C Laurie; Claude Bouchard; Richard S Cooper; Michele K Evans; Vilmundur Gudnason; Sharon L R Kardia; Stephen B Kritchevsky; Daniel Levy; Jeff R O'Connell; Bruce M Psaty; Rob M van Dam; Mario Sims; Donna K Arnett; Dennis O Mook-Kanamori; Tanika N Kelly; Ervin R Fox; Caroline Hayward; Myriam Fornage; Charles N Rotimi; Michael A Province; Cornelia M van Duijn; E Shyong Tai; Tien Yin Wong; Ruth J F Loos; Alex P Reiner; Jerome I Rotter; Xiaofeng Zhu; Laura J Bierut; W James Gauderman; Mark J Caulfield; Paul Elliott; Kenneth Rice; Patricia B Munroe; Alanna C Morrison; L Adrienne Cupples; Dabeeru C Rao; Daniel I Chasman Journal: Am J Hum Genet Date: 2018-02-15 Impact factor: 11.025
Authors: Elisabeth Thiering; Terho Lehtimäki; Marcella Marinelli; Penelope A Lind; Priyakumari Ganesh Parmar; H Rob Taal; Nicholas J Timpson; Laura D Howe; Germaine Verwoert; Ville Aalto; Andre G Uitterlinden; Laurent Briollais; Dave M Evans; Margie J Wright; John P Newnham; John B Whitfield; Leo-Pekka Lyytikäinen; Fernando Rivadeneira; Dorrett I Boomsma; Jorma Viikari; Matthew W Gillman; Beate St Pourcain; Jouke-Jan Hottenga; Grant W Montgomery; Albert Hofman; Mika Kähönen; Nicholas G Martin; Martin D Tobin; Ollie Raitakari; Jesus Vioque; Vincent W V Jaddoe; Marjo-Riita Jarvelin; Lawrence J Beilin; Joachim Heinrich; Cornelia M van Duijn; Craig E Pennell; Debbie A Lawlor; Lyle J Palmer Journal: Circ Cardiovasc Genet Date: 2016-03-11
Authors: Jan Bressler; Nora Franceschini; Ellen W Demerath; Thomas H Mosley; Aaron R Folsom; Eric Boerwinkle Journal: BMC Med Genet Date: 2015-07-23 Impact factor: 2.103
Authors: Cécilia G Maubaret; Klelia D Salpea; Casey E Romanoski; Lasse Folkersen; Jackie A Cooper; Coralea Stephanou; Ka Wah Li; Jutta Palmen; Anders Hamsten; Andrew Neil; Jeffrey W Stephens; Aldons J Lusis; Per Eriksson; Philippa J Talmud; Steve E Humphries Journal: PLoS One Date: 2013-12-12 Impact factor: 3.240